Background/Purpose: Behcet’s disease (BD) is a multi-system inflammatory disease, characterized by recurrent exacerbations affecting several organs including orogenital mucosa, eyes and skin. Two recent genome-wide association study (GWAS) of BD in Turkish and Japanese populations both confirmed the strong association of MHC Class I region and identified two non-HLA common genetic variations with a mild effect on BD. In complex diseases such as BD, multiple factors [e.g. single nucleotide polymorphisms (SNPs), miRNAs, metabolic and epigenetic factors] may target different sets of genes in the same pathway crippling its function and thus causing the disease development. In this regard, we hypothesized that the pathways critical to the mechanisms underlying BD will be conserved within and across populations.  

Methods: To identify these disease-associated pathways, we previously developed a novel methodology that combines nominally significant evidence of genetic association with current knowledge of biochemical pathways, protein-protein interaction networks, and functional information of selected SNPs. Using this methodology, we herein searched for the disease related pathways on two BD GWAS in Turkish and Japanese case–control cohorts by using the list of SNPs providing a P value <0,05. 

Results: Even though there were a few significantly conserved SNPs/genes within and between populations, five of the top ten affected pathways were found to be significant in both populations. The probability of random occurrence of such an event is 5.13E-36. These shared pathways were Notch signaling pathway, focal adhesion, Jak-STAT signaling pathway, long-term potentiation and pathways in cancer. Considering some differences in the clinical manifestations such as more frequent involvement of major vessels in Turkish patients, we observed some correlating rankings in the pathways. The complement and coagulation cascades pathway was identified in 5th and 33rd rankings with P=2.47E-20, P=2.6E-12 in Turkish and Japanese populations, respectively.  

Conclusion: By applying our method on two BD GWAS dataset, here we have shown that while the total number of genome-wide significant genetic associations is limited, identification of the shared pathways between the Turkish and the Japanese populations may help further explaining the general mechanisms of BD pathogenesis. Even though each individual has a unique combination of factors involved in disease development mechanism, most of the targeted pathways that need to be altered by these factors are expected to be conserved. The pathways that are identified by population specific GWAS need to be examined to gain a more comprehensive understanding of BD pathogenesis and their potential to be used as biomarkers and/or drug targets.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-identification-of-pathway-markers-in-behcets-disease-using-genomewide-association-data-from-two-different-populations/